The objective is to study metabolic abnormalities in rheumatoid arthritis, including the hypothesis that hypohistidinemia participates in the pathogenesis of the disease. The approach is based on three findings: (1) The serum histidine concentration is decreased specifically in rheumatoid arthritis and this abnormality is proportional to the activity of the arthritis. (2) L-Histidine (as the histidine-cystine-copper mixture), gold thiomalate, and penicillamine (as the penicillamine disulfide-copper complex) inhibit--and hyaluronic acid augments--the thermal and mechanical denaturation of human gamma-globulin. (3) Oral L-histidine may be beneficial in patients with active rheumatoid arthritis. The following experiments are planned: correlation of the serum and synovial fluid histidine concentrations; study of the serum histidine concentration in systemic lupus erythematosus, scleroderma, etc.; continued study of the treatment of rheumatoid arthritis with oral L-histidine; measurement of the concentration of the histidine-cystine-copper complex in the serum of patients with rheumatoid arthritis; study of the rate of conversion of D-penicillamine to D-penicillamine disulfide in serum in vitro; and determination of the concentration of gamma globulin in the precipitate formed by the mechanical denaturation of synovial fluid. These studies should contribute to a better understanding of the possible role of hypohistidinemia in the pathogenesis of rheumatoid arthritis. BIBLIOGRAPHIC REFERENCES: Gerber DA: Inhibition of denaturation of human gamma globulin by a mixture of L-histidine, L-cystine, and copper, and its clinical implication in rheumatoid arthritis. Arthritis Rheum 19:593-601, 1976. Gerber DA, Gerber MG: Specificity of a low free serum histidine concentration for rheumatoid arthritis. J Chronic Dis 30:115-127, 1977.